The references cited in the present application are not admitted to be prior art to the claimed invention.
It is estimated that about 3% of the world's population is infected with the hepatitis C virus (HCV). (Wasley et al., Semin. Liver Dis. 20:1-16, 2000.) HCV exposure results in an overt acute disease in a small percentage of cases, while in most instances the virus establishes a chronic infection causing liver inflammation and slowly progresses into liver failure and cirrhosis. (Strader et al., ILAR J. 42:107-116, 2001.) Epidemiological surveys indicate an important role for HCV in the onset of hepatocellular carcinoma. (Strader et al., ILAR J. 42:107-116, 2001.)
HCV can be classified into a number of distinct genotypes (1 to 6), and subtypes (a to c). The distribution of the genotypes and subtypes varies both geographically and between risk groups. (Robertson et al., Arch Virol. 143:2493-2503, 1998.)
The HCV genome consists of a single strand RNA about 9.5 kb encoding a precursor polyprotein of about 3000 amino acids. (Choo et al., Science 244:362-364, 1989, Choo et al., Science 244:359-362, 1989.) The HCV polyprotein contains the viral proteins in the order: C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B. Cleavage of the precursor polyprotein results in mature structural and non-structural viral proteins. (Neddermann et al., Biol. Chem. 378:469-476, 1997.)
As part of its infection cycle, HCV enters into a cell. Host cell LDL receptors and CD81 molecules have been identified as putative HCV receptors. The LDL receptor has been suggested to mediate virus internalization via binding to LDL particles that are virus-associated. (Agnello et al., Proc. Natl. Acad. Sci. U.S.A. 96:12766-12771, 1999.) The CD81 molecule has been suggested to bind HCV E2 based on recombinant envelope protein E2 from HCV genotype 1a. (Pileri et al., Science 282:938-941, 1998.)
HCV envelope glycoprotein E2 was found to bind human hepatoma cells independently of CD81. The receptor responsible for E2 binding to human hepatic cells was identified as the human scavenger receptor class B type I (SR-B1). (Scarselli et al., The EMBO Journal 21:5017-5025, 2002.)